CD8+ T cells are critical for effective host defenses against viral infections. Previous studies addressing human immunodeficiency virus (HIV)-induced immune responses in infected individuals have suggested that CD8+ T cells play an important role in controlling viral replication. However, despite an abundance of HIV-specific CD8+ T cells, viral replication is not contained in the majority of HIV-infected individuals in the absence of effective antiretroviral therapy. Active HIV replication is associated with numerous immunologic changes, most notable and consistent of which is an increase in CD8+ T cells expressing CD38. Previous studies have demonstrated that the expression of CD38 on CD8+ T cells is associated with poor prognostic outcome in infected individuals with detectable plasma viremia; however, the relationship between the expression of CD38 and the frequency of HIV-specific CD8+ T cells is unclear. In the present study, we demonstrate a direct correlation between the level of HIV-specific CD8+ T cells and the percentage of CD8+ T cells expressing CD38 in untreated HIV-infected individuals. HIV-specific CD8+ T cells were shown to be evenly distributed between CD38-CD8+ and CD38+CD8+ T cells in patients with a low percentage of CD8+ T cells expressing CD38 whereas their distribution was skewed toward the CD38+CD8+ T cell population in patients with a high percentage of CD8+ T cells expressing CD38. In addition, a direct correlation was observed between the frequency of HIV-specific CD8+ T cells that were found in the CD38+CD8+ T cell population and the percentage of CD8+ T cells expressing CD38. Our data suggest that a substantial proportion of the HIV-specific CD8+ T cells present in the population of CD38+CD8+ T cells in infected individuals with active viral replication arise by HIV-driven aberrant immune activation and may not manifest effective cytolytic activitiy against infected targets, thus providing an explanation why HIV is not successfully contained by CD8+ T cells in such individuals. Therefore, the large proportion of HIV-specific CD8+ T cells that express CD38 may reflect a defective virus-specific immune response in HIV-infected individuals.